CS269728B1 - Method of 7-chloro-6-fluoro-1-(4-fluorophenyl)-1,4-dihydro-4-oxoquinoline-3-carboxylic acid's preparation - Google Patents

Abstract

The solution relates to a method of preparation 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4- -dihydro-4-oxoquinoline-3-carboxylic acid of Formula I CS 269728 B l characterized in that 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4-dibydro-4-oxoquinoline-3-carboxylic acid acid subject diazotization in 30 to 70% solution hydrogen fluoride in pyridine and dehydrogenation heating the resulting solution to temperature of 50 to 90 ° C. Compound of Formula I i it serves as an intermediate for the preparation of antibacterial preparation of difloxacin.

Description

EN 269 728 B1 1

The present invention relates to a process for the preparation of 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of formula I

There is a high potency of a number of substituted 1-aryl-6-fluoro-1,4-dihydro-4-oxo-quinoline-3-carboxylic acids against a wide variety of bacteria. The most active compounds at the 7-position are the cyclic amine residue, often piperazine, and the 4-fluorophenyl group at the 1-position (Hádl, S., Zikán, V .: Czechoslovak. Parm. 36, 180, 1987). A key intermediate for the preparation of these compounds is the compound of formula I. The prior art process for preparing this compound is difficult and is based on 2,4-dihydro-5-fluorobenzoic acid which is poorly available (Chu, DTW and Bpol. J. Med. Chem., 28, 1558 (1985).

The disadvantage of the difficult preparation of the compound of formula (I) and the difficulty in obtaining the starting materials are eliminated by the present invention. According to the invention, the compound of formula (I) can be prepared by diazotizing a solution of readily available 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid in 30-70% solution dry hydrogen fluoride in pyridine, with alkali nitrite and decomposition of the diazonium fluoride thus formed by heating the reaction mixture to a temperature of 50 to 90 ° C, preferably to 70 ° C.

The process of the invention is simple and provides the desired substance in a purifiable form for further processing to difloxacin or similar antibacterial preparations. The examples set forth further details, but the invention is merely illustrative, not limiting. Example 1 To a solution of dry hydrogen fluoride (12 g) in pyridine (13 g) was added 1.66 g (5 mmol) of 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4 at -20 ° C. -dihydro-4-oxoquinoline-3-carboxylic acid, and the mixture was stirred at room temperature for 30 minutes. After cooling to 0 ° C, 0.42 g (6 mmol) of sodium nitrite was added and the mixture was stirred for 30 minutes at room temperature. The temperature was then raised to 70 ° C over a period of 30 minutes and the reaction mixture was kept at this temperature for 1 hour. After cooling, the reaction mixture was poured onto 200 g of ice and allowed to stand for another day, then insoluble matter was sucked off and washed with water. 1.05 g of material (62%) was obtained, mp 260-264 ° C. EXAMPLE 2 To a solution of dry hydrogen fluoride (10 g) in pyridine (5 g) was added 0.99 g (3 mmol) of 1- (4-aminophenyl) -7-chloro-6-fluoro-1, 4-g at 3 ° C. dihydro-4-oxoquinoline-3-carboxylic acid and further worked up in the same manner as in Example 1. 0.6 g (60%) of the same properties as in Example 1 were obtained.

Claims (1)

BACKGROUND OF THE INVENTION Process for preparing 7-chloro-6-fluoro-1- (4-fluorophenyl) -1,4-dihydro-4-oxoquinoline-3-carboxylic acid of Formula I COOH (I). characterized in that 1- (4-aminophenyl) -7-chloro-6-fluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid is diazotized in a 30-70% hydrogen fluoride solution in pyridine and the following isothiazonizate. heating the resulting solution to a temperature of 90 to 90 ° C.